1. Field of the Invention
The present invention relates to a semipermeable membrane for blood treatment which exhibits little change in performance upon drying and reduced elution of a hydrophilic polymer therefrom; a dialyzer for use in blood treatment using the same; and a processes for producing a dialyzer having incorporated therein a semipermeable membrane which exhibits little change in performance before and after drying and reduced elution of a hydrophilic polymer therefrom.
2. Description of the Related Art
As a material for a semipermeable membrane for blood treatment such as an artificial kidney, there have been used a number of materials. For example, a natural material cellulose and its derivatives, e.g., cellulose diacetate and cellulose triacetate, were originally used, and synthetic polymers were then developed, such as polysulfone, polymethyl methacrylate (PMMA) and polyacrylonitrile. Recently, modified cellulose membranes have also been used which is prepared by treating cellulose with polyethylene glycol (PEG) or the like to modify the compatibility to blood. In semipermeable membranes for blood treatment in patients suffering from chronic renal failure, attempts have been made to reduce the leakage of albumin to a minimum while positively removing low molecular proteins other than albumin. In addition to such improvement in the membranes, hemodiafiltration (HDF) procedures and push-and-pull procedures have been developed for increasing the dialysis efficiency and positive removal of undesirable low molecular proteins. Polysulfone, which has a high water permeability, is now widely used since it meets the above-mentioned requirements. In a polysulfone membrane, a hydrophilic polymer is generally blended to impart an affinity for blood to the membrane. However, the polysulfone membrane has such a defect that once it is dried the properties tend to be changed to a great extent. Hence, it is difficult to produce a dry type of polysulfone membrane dialyzer which is light-weight and easy to handle.
Accordingly, it is an object of the present invention to provide a dialyzer using a dry or semi-dry type of semipermeable membrane which has advantages such as light-weight and resistance to freeze, wherein the semipermeable membrane is improved in water permeability and dialyze performance (which are poor in a conventional one) to the same level as those of a wet type one.
It is another object of the present invention to provide a dry or semi-dry type of dialyzer having advantages such as light-weight and resistance to freeze, wherein the dialyzer is improved in water permeability and dialyze performance (which are poor in a conventional one) to the same level as those of a wet-type one and exhibits a reduced elution of a hydrophilic polymer therefrom.
That is, in an aspect of the present invention, there is provided a dialyzer for blood treatment having incorporated therein a semipermeable membrane which comprises a hydrophobic polymer and a hydrophilic polymer, the water permeating performance of the semipermeable membrane after drying being xc2xd or higher relative to that before drying and the dialyzer satisfying any of the following requirements:
(A) the vitamin B12 clearance is not smaller than 135 ml/min per 1.6 m2; and
(B) the amount of the hydrophilic polymer that is eluted from the semipermeable membrane is not higher than 10 ppm.
In another aspect of the present invention, there is provided a process for producing a dialyzer having incorporated therein a semipermeable membrane which comprises a hydrophobic polymer and a hydrophilic polymer, the process comprising:
drying the semipermeable membrane; and
saturating the dried semipermeable membrane with water ratio of not smaller than 100% based on the dry weight of the semipermeable membrane, providing an inert gas atmosphere to the inside of the dialyzer, and then irradiating the semipermeable membrane with gamma-ray in the inert gas atmosphere.
In still another aspect of the present invention, there is provided a process for producing a hollow fiber membrane for use in blood treatment through dry/wet spinning from a spinning solution comprising 15 to 18% by weight of a hydrophobic polymer and 4 to 8% by weight of a hydrophilic polymer, the dry zone being filled with dry mist.
In the present invention, the hydrophobic polymer to be used in the semipermeable membrane includes a number of engineering plastics, such as polysulfone, polyamide, polyimide, polyphenyl ether and polyphenylene sulfide. Preferably, the hydrophobic polymer is polysulfone represented by the formula below, which shows the skeleton of the polysulfone. Polysulfone derivatives in which the benzene ring in the skeleton is modified are also usable in the present invention. 
The hydrophilic polymer to be used in the semipermeable membrane includes, for example, polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose and polyvinyl pyrrolidone, which may be used alone or in combination. Polyvinyl pyrrolidone (hereinafter, sometimes referred to as xe2x80x9cPVPxe2x80x9d) is preferred since it is relatively high in industrial availability. It is preferable to use two or more of hydrophilic polymers having different molecular weights. In this instance, the hydrophilic polymers preferably have different weight average molecular weights from one another by five times or more.
The spinning solution to be used for the preparation of the semipermeable membrane preferably comprises a hydrophobic polymer, a hydrophilic polymer, a solvent and an additive. The solvent may be an amphiprotic solvent which can fully dissolve all of the hydrophobic polymer, the hydrophilic polymer and the additive. Specific examples of the solvent include dimethylacetamide, dimethylformamide, dimethylsulfoxide, acetone, acetaldehyde and 2-methyl pyrrolidone. Dimethylacetamide is particularly preferred from the viewpoints of safety, stability and toxicity. The additive may be one which is a poor solvent for the hydrophobic polymer but is miscible with the hydrophilic polymer, such as an alcohol, glycerin, water and an ester. Water is particularly preferred from the viewpoint of process suitability.
The viscosity of the spinning solution for membrane production may depend on the molecular weight of the hydrophilic polymer, since commercially available hydrophilic polymers have low molecular weights. A decreased viscosity of the spinning solution could cause breakage or swinging of fibers during the preparation of a hollow fiber membrane, leading to a decreased stability of the resulting hollow fiber membrane. Accordingly, when PVP is used as the hydrophilic polymer, PVP with a high molecular weight is preferred. When two or more types of PVP are used in a mixture, the PVP mixture preferably has an average molecular weight of 200,000 or higher.
Next, the contents of the hydrophobic and hydrophilic polymers in the spinning solution is described. As stated above, as the polymer content increases, a membrane can be formed more effectively but the porosity of the resulting membrane decreases, leading to a decreased water permeability. Accordingly, there is an optimum range for the polymer content. To obtain a membrane that can exert both a high permselectivity and a low albumin permeability even when dried, like one produced in the present invention, the concentration of the hydrophobic polymer is preferably 10 to 20% by weight, more preferably 12 to 18% by weight, and the concentration of the hydrophilic polymer is preferably 2 to 20% by weight, more preferably 3 to 15% by weight. In the case where two or more hydrophilic polymers having different molecular weights are used, it is preferable that the content of hydrophilic polymers having molecular weights of 100,000 or higher in the spinning solution is 1 to 10% by weight. If this content is too large, the viscosity of the spinning solution increases, which may cause difficulty in formation of a membrane, as well as decrease in water permeability and diffusion performance. On the contrary, if this content is too small, it becomes impossible to construct a desirable network structure desired for the permeation of medium-to-high molecular weight uremia-toxic proteins.
When the hydrophobic polymer is a polysulfonic resin and the hydrophilic polymer is polyvinyl pyrrolidone, preferably the polyvinyl pyrrolidone in the semipermeable membrane is 1 to 10% by weight based on the content of the polysulfonic resin.
An embodiment of the process for preparing the semipermeable membrane is described hereinbelow. A spinning solution having a composition as mentioned above, along with a core solution, is extruded from a spinneret through an annular double slit tube to form a hollow fiber membrane. The membrane is washed with water, dried, and then crimped. The crimped membrane is taken up and cut to an appropriate length. The cut membranes are placed in a module case, in which both end faces of the bundle of the membranes are sealed with a potting material. In this manner, a hollow fiber membrane module is produced.
Preferably, the membrane is formed by a dry/wet spinning process, in which a dry zone is filled with dry mist. The dry mist refers to a mist-like material comprising water particles of 10 xcexcm or smaller. The introduction of the dry mist into the dry zone can generate cores which may play an important role in the process for forming an outer surface of the hollow fiber membrane. PVP can coagulate around the cores to form PVP phases; thus, phase separation occurs in the dry zone. Subsequently, the fully grown PVP phases are removed in the coagulation bath, generating large pores. A conventional polysulfone dialyzing membrane generally has an asymmetric structure, where the permeation of material is controlled only through the inner surface. However, by providing such large pores on the outer surface of the membrane, an outer support layer having a coarse, porous structure can be formed. This structure enables a substance to be transferred through the membrane by diffusion more readily, thus providing an increased permeation performance to the finished dialyzing membrane.
In the present invention, for the formation of the hollow fiber membrane (not xe2x80x9cmodulexe2x80x9d), a conventional process including the treatment of the hollow fiber membrane with a moisture-retaining agent but not including any drying of the membrane is not employed and, instead, a process including the positive drying of the membrane is employed. As a result, a hollow fiber membrane of which water permeating performance after drying is xc2xd or higher relative to that before drying can be produced. Preferably, it should be 75% or higher, and more preferably it should be 90% or higher. In the process of the present invention, since the membrane is dried without the treatment with a moisture-retaining gent, the spinning solution should be designed taking the shrinking of the dried membrane in consideration. When the semipermeable membrane is used in this state particularly in an artificial kidney, however, a considerable amount of the hydrophilic polymer may diffuse from the membrane. For the purpose of reducing such elution, it is preferable that the membrane be subjected to a cross-linking treatment with gamma-ray irradiation, electron beam irradiation, or heat or chemical treatment. If gamma-ray is irradiated in the presence of air (i.e., oxygen), the breakage of the backbone of the hydrophilic polymer could occur by the action of excited oxygen radicals, resulting in the decomposition of the polymer. To solve this problem, it is preferable to saturate the membrane with water ratio of not smaller than 100% and not higher than 1000%, more preferably 100 to 600%, still more preferably 100 to 400% based on the dry weight of the membrane, replace the atmospheric air with an inert gas, and then irradiate the membrane with gamma-ray. Thus, elution of the hydrophilic polymer from the membrane can be prevented effectively. As the inert gas, nitrogen, argon, helium and carbon dioxide are preferably used. Nitrogen, which is inexpensive, is particularly preferred. The exposure dose of gamma-ray is preferably 10 to 50 KGy, more preferably 10 to 30 KGy. Since the cross-linking treatment induces the binding between the hydrophobic polymer and the hydrophilic polymer, elution of the hydrophilic polymer from the membrane can be reduced. The forced elution test of the membrane as described below demonstrated that any peak indicating the presence of the hydrophilic polymer eluted from the membrane was not observed. Accordingly, a semipermeable membrane having an elution amount of not higher than 10 ppm can be manufactured. The term xe2x80x9can elution amountxe2x80x9d refers to the amount of the hydrophilic polymer in an extract that is prepared by dispersing or dissolving a certain amount of hollow fibers into a solvent which is a good solvent for both the hydrophobic and the hydrophilic polymers, has a solubility against the both polymers of not smaller than 0.5 g/ml and is immiscible with water, and then extracting the hydrophilic polymer from the solution with a certain amount of aqueous phase (0.1N ammonium chloride solution, pH 9.5) to give the extract. In the case where the hydrophilic polymer is a mixture of polysulfone and polyvinyl pyrrolidone, the good solvent is preferably methylene chloride.
The semipermeable membrane prepared as mentioned above characteristically exhibits good performance as a membrane for blood treatment, such as good diffusing capacity for uremia-causing substances and diffusion resistance against a useful protein albumin, and has a reduced elution of the hydrophilic polymer therefrom, due to the network structure formed with the hydrophobic and hydrophilic polymers. If the albumin permeability exceeds 3%, physical conditions of hypoalbuminemia patients or the nutritive conditions of elderly persons may affected. Therefore, the albumin permeability is preferably 3% or lower. The uremia-causing substance or uremic toxin may be urea, creatinine or uric acid. As the indicator of the substance permeation, vitamin B12 may be mentioned. In the semipermeable membrane of the present invention, the vitamin B12 clearance can be 135 ml/min or higher per 1.6 m2. The clearance of urea, creatinine and uric acid is preferably 188, 175 and 165 ml/min, respectively, or higher per 1.6 m2 in the practical viewpoint.
In order to achieve the above-stated properties, the content of the hydrophilic polymer in the membrane after the cross-linking should be 1 to 10%, and is preferably 2 to 6% by weight. Too small content may cause reduction in wetting ability against water and coagulation may occur upon contacting with blood. It is also preferable that the membrane after the cross-linking contain insoluble substances in a concentration of 5 to 15% by weight.
A stated above, the semipermeable membrane for blood treatment according to the present invention can exhibit a water permeability after drying of xc2xd or higher relative to that before drying, by employing a step of drying the membrane in the state where no moisture-retaining agent is attached to the membrane and a step of cross-linking the dried membrane after moisture conditioning (i.e., saturating with water). As a result, the membrane can be applied to a dialyzer which exhibits good properties such as decreased water permeability and less leaking of substances eluted from the membrane even when used after drying. The membrane of the present invention can be used in a dry or semi-dry state (as used herein, the term xe2x80x9csemi-dry statexe2x80x9d refers to a state where water is contained in the membrane but spaces between the hollow fibers are filled with a gas). Accordingly, a semipermeable membrane can be provided which is light-weight, almost free from the problem of freeze and easy to handle and has excellent performance. The production of such a semipermeable membrane may contribute to the reduced cost of the dialysis. Moreover, the membrane can exhibits a high dialyze performance at various temperatures and sterilization conditions since degradation in dialyze performance hardly occurs by drying. On the other hand, in the application to the treatment of a human body, elution of the hydrophilic polymer (a foreign substance to the body) can be reduced, leading to increased safety of the membrane as medical equipment. The dialyzer according to the present invention is applicable to medical apparatuses for blood treatment, such as an artificial kidney, a plasma separative membrane and a carrier for extracorporeal circulation adsorptive separation.